The proposed research deals with the metabolism and function of nuclear proteins in intestinal epithelial cells - with particular attention to changes in chromosomal proteins during early stages of colon carcinogenesis induced by 1,2-dimethylhydrazine. The objective is to relate events in carcinogenesis to changes in DNA-associated proteins concerned with transcriptional control and with DNA synthesis. Experimental approaches begin with isolations of discrete nuclear fractions derived from different cell types in the epithelium of the large colon. The methods allow a separation of nuclei at different stages of cell differentiation in the different layers of the crypt and luminar surface of normal, preneoplastic, and tumor tissues. The acidic (non-histone) proteins of the various nuclear types are being analyzed in terms of heterogeneity, molecular-weight distribution, rates of synthesis and phosphorylation, DNA-binding affinities, effects on transcription, response to carcinogens, and control of nuclear activity by Vitamin A and Vitamin D. Characteristic changes in nuclear proteins ensuing soon after exposure to the carcinogen, 1,2-dimethylhydrazine, are being detected in animals long before morphological indications of malignancy. A search for similar changes in human colonic mucosal cells may constitute a basis for the development of procedures for early diagnosis of preneoplastic changes. A closely-related aspect of the program deals with the mechanism of carcinogenesis. The effects of 1,2-dimethylhydrazine include multiple modifications of structure of DNA binding proteins, some of which are now being characterized.